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Echinocandins for prevention and treatment of invasive fungal infections
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Melissa D. Johnson, John Mohr, Ahmad Mourad
Preclinical studies with rezafungin (CD-101), a new echinocandin in development (NCT02734862, NCT02733432), suggest that it has an improved safety profile than other echinocandins. This, in part, is due to its structural stability, infrequent Cyp450 enzyme interactions, as well as not forming reactive intermediates like the other echinocandins [169]. A phase I clinical trial has shown doses of rezafungin (CD-101) of 400 mg once weekly for up to 3 weeks to be very well tolerated with no incidents of serious or severe adverse events and none requiring discontinuation of therapy. It’s long half-life and linear pharmacokinetics suggest it may require less frequent dosing for therapeutic success [170].
Existing and emerging therapies for the treatment of invasive candidiasis and candidemia
Published in Expert Opinion on Emerging Drugs, 2022
David De Bels, Evelyne Maillart, Françoise Van Bambeke, Sebastien Redant, Patrick M. Honoré
Rezafungin or CD101 is a derivative of anidulafungin showing improved stability and solubility and prolonged half-life (133 h). It shows an activity comparable to the other echinocandins against most clinically relevant Candida species, including C. albicans, C. glabrata, C. krusei, and C. tropicalis, and also cross-resistance with caspofungin and anidulafungin. Interestingly, it is more potent than the other echinocandins against C. auris with MIC90 of 0.5 µg/ml [80] Available clinical data show a quite robust safety. In clinical trials in phases 1 and 2, rezafungin was administered IV with a loading dose of 400 mg and then a weekly dose of 200 mg. In the STRIVE phase 2 study, adults with systemic signs and mycological confirmation of candidemia and/or invasive candidiasis were randomized to rezafungin 400 mg QWk (400 mg), rezafungin 400 mg on week 1 then 200 mg QWk (400/200 mg), or caspofungin (70 mg loading dose followed by 50 mg daily for at most 4 weeks). Candidemia was cleared in 19.5 and 22.8 hours in rezafungin and caspofungin patients, respectively. Cure rates were 60.5% for rezafungin 400 mg, 76.1% for rezafungin 400/200 mg, and 67.2% for caspofungin [81]. A phase 3 trial has recently been completed comparing rezafungin with caspofungin in invasive candidiasis and candidemia and showed non-inferiority regarding all-Cause Mortality at Day 30; and an adequate global cure at Day 14. Another phase 3 trial is ongoing to evaluate rezafungin once weekly as a monotherapy for the prophylaxis of fungal infections.
Azole resistance in Aspergillus species: promising therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Shirisha Pasula, Pranatharthi H. Chandrasekar
It is a new β-glucan synthase inhibitor that is chemically related to anidulafungin, with better stability, tissue penetration, and PK/PD pharmacometrics [57]. It has long half-life of more than 100 hours enabling once weekly administration. Rezafungin has activity against Candida, Aspergillus, and Pneumocystis. It has potent invitro activity against multidrug resistant A. fumigatus [57].This in vitro activity has also translated into in vivo efficacy in a murine model of disseminated aspergillosis secondary to a clinical A. fumigatus isolate harboring a TR34/L98H mutation [48,58]. Like echinocandins, it is available as an intravenous formulation. Rezafungin is currently in phase III clinical trial to evaluate its efficacy and safety versus the standard antimicrobial regimen for the prevention of invasive fungal diseases in subjects undergoing allogeneic stem cell transplantation (NCT04368559).
How urgent is the need for new antifungals?
Published in Expert Opinion on Pharmacotherapy, 2021
Adam G. Stewart, David L. Paterson
Olorofim is a promising agent with a new mechanism of action and favorable pharmacokinetics. Given its potent activity against mold species, it could be well positioned for future use in individuals with invasive mold infection that is refractory or intolerant to standard therapy (i.e. use as salvage), or those infected with pan-resistant mold species (e.g. L. prolificans). Ibrexafungerp and fosmanogepix are both novel broad-spectrum antifungals with good in vitro and in vivo activity against C. auris and could be used for invasive candidiasis due to C. auris in the future as first-line therapy. Rezafungin is an echinocandin with activity against P. jirovecii that can be dosed once weekly. Its future role is likely in antifungal prophylaxis in high-risk patients; however, it may also be suitable for outpatient management of invasive fungal disease. The development of encochleated amphotericin B is exciting as it promises the ability to deliver this broad-spectrum antifungal orally and with less toxicity. Its future use may be in a wide variety of yeast and mold infections, particularly as oral step-down therapy. Oral therapy for patients with infections due to Cryptococcus spp. and the Mucorales could be an area of great value for this drug.